Development of the data registry for the Cardiac Neurodevelopmental Outcome Collaborative.

Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.

Factors Associated With Attendance for Cardiac Neurodevelopmental Evaluation.

BACKGROUND AND OBJECTIVES: Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending neurodevelopmental follow-up are limited. This study aims to estimate the attendance rate for a toddler neurodevelopmental evaluation in a contemporary multicenter cohort and to assess patient and center level factors associated with attending this evaluation. METHODS: This is a retrospective cohort study of children born between September 2017 and September 2018 who underwent cardiopulmonary bypass in their first year of life at a center contributing data to the Cardiac Neurodevelopmental Outcome Collaborative and Pediatric Cardiac Critical Care Consortium clinical registries. The primary outcome was attendance for a neurodevelopmental evaluation between 11 and 30 months of age. Sociodemographic and medical characteristics and center factors specific to neurodevelopmental program design were considered as predictors for attendance. RESULTS: Among 2385 patients eligible from 16 cardiac centers, the attendance rate was 29.0% (692 of 2385), with a range of 7.8% to 54.3% across individual centers. In multivariable logistic regression models, hospital-initiated (versus family-initiated) scheduling for neurodevelopmental evaluation had the largest odds ratio in predicting attendance (odds ratio = 4.24, 95% confidence interval, 2.74-6.55). Other predictors of attendance included antenatal diagnosis, absence of Trisomy 21, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, longer postoperative length of stay, private insurance, and residing a shorter distance from the hospital. CONCLUSIONS: Attendance rates reflect some improvement but remain low. Changes to program infrastructure and design and minimizing barriers affecting access to care are essential components for improving neurodevelopmental care and outcomes for children with congenital heart disease.

Placental delayed villous maturation is associated with fetal congenital heart disease.

BACKGROUND: The placenta is crucial for the overall development and lifelong health of the fetus. Abnormal placental development and function occur in pregnancies with fetal congenital heart disease. However, studies that use standardized diagnostic criteria and incorporate control populations are lacking. This limits the generalizability of current research and the ability to determine the specific placental abnormalities associated with congenital heart disease. OBJECTIVE: This study applied consensus statement guidelines (known as the Amsterdam criteria) for placental pathology interpretation to compare the frequency and pattern of abnormalities in pregnancies with fetal congenital heart disease to demographically matched control pregnancies and evaluate for differences in placental abnormalities by cardiac physiology. STUDY DESIGN: A single-center retrospective cohort study was conducted from January 2013 to June 2019. Infants with a prenatal diagnosis of moderate-severe congenital heart disease who were born at ≥37 weeks of gestation were included. A control group born at ≥37 weeks of gestation but without fetal congenital heart disease or other major pregnancy complications was matched to the congenital heart disease group on maternal race and ethnicity and infant sex. Using the Amsterdam criteria, placental pathology findings were categorized as delayed villous maturation, maternal vascular malperfusion, fetal vascular malperfusion, and inflammatory lesions. The frequency of placental abnormalities was compared between groups, and logistic regression was performed to evaluate the association of clinical and sociodemographic factors with delayed villous maturation, maternal vascular malperfusion, and fetal vascular malperfusion. RESULTS: There were 194 pregnancies with fetal congenital heart disease and 105 controls included, of whom 83% in the congenital heart disease group and 82% in the control group were of non-Hispanic White race and ethnicity. Compared with controls, pregnancies with fetal congenital heart disease had higher rates of delayed villous maturation (6% vs 19%; P<.001) and maternal vascular malperfusion (19% vs 34%; P=.007) but not fetal vascular malperfusion (6% vs 10%; P=.23). Infants with congenital heart disease with 2-ventricle anatomy displayed the highest odds of delayed villous maturation compared with controls (odds ratio, 5.5; 95% confidence interval, 2.2-15.7; P<.01). Maternal vascular malperfusion was 2.2 times higher (P=.02) for infants with 2-ventricle anatomy and 2.9 times higher (P=.02) for infants with single-ventricle physiology with pulmonic obstruction. Within the congenital heart disease group, delayed villous maturation was associated with higher maternal body mass index, polyhydramnios, larger infant birth head circumference, and infant respiratory support in the delivery room, whereas maternal vascular malperfusion was associated with oligohydramnios. In multivariable models adjusting for cardiac diagnosis, associations of delayed villous maturation persisted for infant birth head circumference (odds ratio, 1.2; 95% confidence interval, 1.0-1.5; P=.02) and infant respiratory support in the delivery room (odds ratio, 3.0; 95% confidence interval, 1.3-6.5; P=.007). CONCLUSION: Pregnancies with fetal congenital heart disease displayed higher rates of delayed villous maturation and maternal vascular malperfusion than controls, suggesting that placental maldevelopment may relate to maternal factors. Future investigations are needed to determine the association of these abnormalities with postnatal infant outcomes.

Trajectories of Maternal and Paternal Psychological Distress After Fetal Diagnosis of Moderate-Severe Congenital Heart Disease.

OBJECTIVE: The aim of this study was to compare trajectories of maternal and paternal psychological distress after prenatal diagnosis of fetal moderate-severe congenital heart disease (CHD), from pregnancy through early-mid infancy. METHODS: Pregnant women who received a prenatal diagnosis of fetal moderate-severe CHD, and their partners, were enrolled in a prospective, longitudinal study. Symptoms of psychological distress were measured twice during pregnancy and twice after birth, using the Depression Anxiety Stress Scales (DASS-42). Patterns and predictors of psychological distress were examined using generalized hierarchical linear modeling. RESULTS: Psychological distress was present in 42% (18/43) of mothers and 22% (8/36) of fathers at least once during the study. The rates of distress did not differ between mothers and fathers. There was also no change in probability of distress over time or difference in distress trajectories between mothers and fathers. However, individual trajectories demonstrated considerable variability in symptoms for both mothers and fathers. Predictors of psychological distress included low social support for mothers and a history of mental health conditions for fathers. CONCLUSIONS: Parents who receive a prenatal diagnosis of fetal CHD commonly report symptoms of psychological distress from the time of diagnosis through early-mid infancy and display highly variable trajectories. These data suggest that early and repeated psychological screening is important once a fetal CHD diagnosis is made and that providing mental health and social support to parents may be an important component of their ongoing care.

Optimizing Neurodevelopmental Outcomes in Neonates With Congenital Heart Disease.

Neurodevelopmental impairment is a common and important long-term morbidity among infants with congenital heart disease (CHD). More than half of those with complex CHD will demonstrate some form of neurodevelopmental, neurocognitive, and/or psychosocial dysfunction requiring specialized care and impacting long-term quality of life. Preventing brain injury and treating long-term neurologic sequelae in this high-risk clinical population is imperative for improving neurodevelopmental and psychosocial outcomes. Thus, cardiac neurodevelopmental care is now at the forefront of clinical and research efforts. Initial research primarily focused on neurocritical care and operative strategies to mitigate brain injury. As the field has evolved, investigations have shifted to understanding the prenatal, genetic, and environmental contributions to impaired neurodevelopment. This article summarizes the recent literature detailing the brain abnormalities affecting neurodevelopment in children with CHD, the impact of genetics on neurodevelopmental outcomes, and the best practices for neonatal neurocritical care, focusing on developmental care and parental support as new areas of importance. A framework is also provided for the infrastructure and resources needed to support CHD families across the continuum of care settings.

Quantification of sulcal emergence timing and its variability in early fetal life: Hemispheric asymmetry and sex difference.

Human fetal brains show regionally different temporal patterns of sulcal emergence following a regular timeline, which may be associated with spatiotemporal patterns of gene expression among cortical regions. This study aims to quantify the timing of sulcal emergence and its temporal variability across typically developing fetuses by fitting a logistic curve to presence or absence of sulcus. We found that the sulcal emergence started from the central to the temporo-parieto-occipital lobes and frontal lobe, and the temporal variability of emergence in most of the sulci was similar between 1 and 2 weeks. Small variability (< 1 week) was found in the left central and postcentral sulci and larger variability (>2 weeks) was shown in the bilateral occipitotemporal and left superior temporal sulci. The temporal variability showed a positive correlation with the emergence timing that may be associated with differential contributions between genetic and environmental factors. Our statistical analysis revealed that the right superior temporal sulcus emerged earlier than the left. Female fetuses showed a trend of earlier sulcal emergence in the right superior temporal sulcus, lower temporal variability in the right intraparietal sulcus, and higher variability in the right precentral sulcus compared to male fetuses. Our quantitative and statistical approach quantified the temporal patterns of sulcal emergence in detail that can be a reference for assessing the normality of developing fetal gyrification.

Partnering With Stakeholders to Inform the Co-Design of a Psychosocial Intervention for Prenatally Diagnosed Congenital Heart Disease.

Input from diverse stakeholders is critical to the process of designing healthcare interventions. This study applied a novel mixed-methods, stakeholder-engaged approach to co-design a psychosocial intervention for mothers expecting a baby with congenital heart disease (CHD) and their partners to promote family wellbeing. The research team included parents and clinicians from 8 health systems. Participants were 41 diverse parents of children with prenatally diagnosed CHD across the 8 health systems. Qualitative data were collected through online crowdsourcing and quantitative data were collected through electronic surveys to inform intervention co-design. Phases of intervention co-design were: (I) Engage stakeholders in selection of intervention goals/outcomes; (II) Engage stakeholders in selection of intervention elements; (III) Obtain stakeholder input to increase intervention uptake/utility; (IV) Obtain stakeholder input on aspects of intervention design; and (V) Obtain stakeholder input on selection of outcome measures. Parent participants anticipated the resulting intervention, HEARTPrep, would be acceptable, useful, and feasible for parents expecting a baby with CHD. This model of intervention co-design could be used for the development of healthcare interventions across chronic diseases.

Fetal Brain Volume Predicts Neurodevelopment in Congenital Heart Disease.

BACKGROUND: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), but postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD. METHODS: Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain magnetic resonance imaging and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and the Adaptive Behavior Assessment System, Third Edition (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth measures, and medical history. RESULTS: The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but this was not noted in the control group. Fetal brain volume predicted 10% to 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18% to 45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains. CONCLUSIONS: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.

Optimal Method for Fetal Brain Age Prediction Using Multiplanar Slices From Structural Magnetic Resonance Imaging.

The accurate prediction of fetal brain age using magnetic resonance imaging (MRI) may contribute to the identification of brain abnormalities and the risk of adverse developmental outcomes. This study aimed to propose a method for predicting fetal brain age using MRIs from 220 healthy fetuses between 15.9 and 38.7 weeks of gestational age (GA). We built a 2D single-channel convolutional neural network (CNN) with multiplanar MRI slices in different orthogonal planes without correction for interslice motion. In each fetus, multiple age predictions from different slices were generated, and the brain age was obtained using the mode that determined the most frequent value among the multiple predictions from the 2D single-channel CNN. We obtained a mean absolute error (MAE) of 0.125 weeks (0.875 days) between the GA and brain age across the fetuses. The use of multiplanar slices achieved significantly lower prediction error and its variance than the use of a single slice and a single MRI stack. Our 2D single-channel CNN with multiplanar slices yielded a significantly lower stack-wise MAE (0.304 weeks) than the 2D multi-channel (MAE = 0.979, p < 0.001) and 3D (MAE = 1.114, p < 0.001) CNNs. The saliency maps from our method indicated that the anatomical information describing the cortex and ventricles was the primary contributor to brain age prediction. With the application of the proposed method to external MRIs from 21 healthy fetuses, we obtained an MAE of 0.508 weeks. Based on the external MRIs, we found that the stack-wise MAE of the 2D single-channel CNN (0.743 weeks) was significantly lower than those of the 2D multi-channel (1.466 weeks, p < 0.001) and 3D (1.241 weeks, p < 0.001) CNNs. These results demonstrate that our method with multiplanar slices accurately predicts fetal brain age without the need for increased dimensionality or complex MRI preprocessing steps.

Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia.

Ensuring comfort for neonates undergoing therapeutic hypothermia (TH) after neonatal encephalopathy (NE) exemplifies a vital facet of neonatal neurocritical care. Physiologic markers of stress are frequently present in these neonates. Non-pharmacologic comfort measures form the foundation of care, benefitting both the neonate and parents. Pharmacological sedatives may also be indicated, yet have the potential to both mitigate and intensify the neurotoxicity of a hypoxic-ischemic insult. Morphine represents current standard of care with a history of utilization and extensive pharmacokinetic data to guide safe and effective dosing. Dexmedetomidine, as an alternative to morphine, has several appealing characteristics, including neuroprotective effects in animal models; robust pharmacokinetic studies in neonates with NE treated with TH are required to ensure a safe and effective standard dosing approach. Future studies in neonates treated with TH must address comfort, adverse events, and long-term outcomes in the context of specific sedation practices.

A Deep Attentive Convolutional Neural Network for Automatic Cortical Plate Segmentation in Fetal MRI.

Fetal cortical plate segmentation is essential in quantitative analysis of fetal brain maturation and cortical folding. Manual segmentation of the cortical plate, or manual refinement of automatic segmentations is tedious and time-consuming. Automatic segmentation of the cortical plate, on the other hand, is challenged by the relatively low resolution of the reconstructed fetal brain MRI scans compared to the thin structure of the cortical plate, partial voluming, and the wide range of variations in the morphology of the cortical plate as the brain matures during gestation. To reduce the burden of manual refinement of segmentations, we have developed a new and powerful deep learning segmentation method. Our method exploits new deep attentive modules with mixed kernel convolutions within a fully convolutional neural network architecture that utilizes deep supervision and residual connections. We evaluated our method quantitatively based on several performance measures and expert evaluations. Results show that our method outperforms several state-of-the-art deep models for segmentation, as well as a state-of-the-art multi-atlas segmentation technique. We achieved average Dice similarity coefficient of 0.87, average Hausdorff distance of 0.96 mm, and average symmetric surface difference of 0.28 mm on reconstructed fetal brain MRI scans of fetuses scanned in the gestational age range of 16 to 39 weeks (28.6± 5.3). With a computation time of less than 1 minute per fetal brain, our method can facilitate and accelerate large-scale studies on normal and altered fetal brain cortical maturation and folding.

Practical approaches to sedation and analgesia in the newborn.

The prevention, assessment, and treatment of neonatal pain and agitation continues to challenge clinicians and researchers. Substantial progress has been made in the past three decades, but numerous outstanding questions remain. In this setting, clinicians must establish safe and compassionate standardized practices that consider available efficacy data, long-term outcomes, and research gaps. Novel approaches with limited data must be carefully considered against historic standards of care with robust data suggesting limited benefit and clear adverse effects. This review summarizes available evidence while suggesting practical clinical approaches to pain assessment and avoidance, procedural analgesia, postoperative analgesia, sedation during mechanical ventilation and therapeutic hypothermia, and the issues of tolerance and withdrawal. Further research in all areas represents an urgent priority for optimal neonatal care. In the meantime, synthesis of available data offers clinicians challenging choices as they balance benefit and risk in vulnerable critically ill neonates.

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease.

OBJECTIVE: Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development. METHODS: From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; "CHD-other," with other CHD diagnoses; "CHD-related," healthy with a CHD family history; and "optimal control," healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables. RESULTS: HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard error = 4.3%], p < 0.01) and intermediate (-13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (-7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery. INTERPRETATION: Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143-157.

Fetal Cortical Plate Segmentation Using Fully Convolutional Networks With Multiple Plane Aggregation.

Fetal magnetic resonance imaging (MRI) has the potential to advance our understanding of human brain development by providing quantitative information of cortical plate (CP) development in vivo. However, for a reliable quantitative analysis of cortical volume and sulcal folding, accurate and automated segmentation of the CP is crucial. In this study, we propose a fully convolutional neural network for the automatic segmentation of the CP. We developed a novel hybrid loss function to improve the segmentation accuracy and adopted multi-view (axial, coronal, and sagittal) aggregation with a test-time augmentation method to reduce errors using three-dimensional (3D) information and multiple predictions. We evaluated our proposed method using the ten-fold cross-validation of 52 fetal brain MR images (22.9-31.4 weeks of gestation). The proposed method obtained Dice coefficients of 0.907 ± 0.027 and 0.906 ± 0.031 as well as a mean surface distance error of 0.182 ± 0.058 mm and 0.185 ± 0.069 mm for the left and right, respectively. In addition, the left and right CP volumes, surface area, and global mean curvature generated by automatic segmentation showed a high correlation with the values generated by manual segmentation (R 2 > 0.941). We also demonstrated that the proposed hybrid loss function and the combination of multi-view aggregation and test-time augmentation significantly improved the CP segmentation accuracy. Our proposed segmentation method will be useful for the automatic and reliable quantification of the cortical structure in the fetal brain.

In vivo characterization of emerging white matter microstructure in the fetal brain in the third trimester.

The third trimester of pregnancy is a period of rapid development of fiber bundles in the fetal white matter. Using a recently developed motion-tracked slice-to-volume registration (MT-SVR) method, we aimed to quantify tract-specific developmental changes in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and volume in third trimester healthy fetuses. To this end, we reconstructed diffusion tensor images from motion corrected fetal diffusion magnetic resonance imaging data. With an approved protocol, fetal MRI exams were performed on healthy pregnant women at 3 Tesla and included multiple (2-8) diffusion scans of the fetal head (1-2 b = 0 s/mm2 images and 12 diffusion-sensitized images at b = 500 s/mm2 ). Diffusion data from 32 fetuses (13 females) with median gestational age (GA) of 33 weeks 4 days were processed with MT-SVR and deterministic tractography seeded by regions of interest corresponding to 12 major fiber tracts. Multivariable regression analysis was used to evaluate the association of GA with volume, FA, and ADC for each tract. For all tracts, the volume and FA increased, and the ADC decreased with GA. Associations reached statistical significance for: FA and ADC of the forceps major; volume and ADC for the forceps minor; FA, ADC, and volume for the cingulum; ADC, FA, and volume for the uncinate fasciculi; ADC of the inferior fronto-occipital fasciculi, ADC of the inferior longitudinal fasciculi; and FA and ADC for the corticospinal tracts. These quantitative results demonstrate the complex pattern and rates of tract-specific, GA-related microstructural changes of the developing white matter in human fetal brain.

Temporal Patterns of Emergence and Spatial Distribution of Sulcal Pits During Fetal Life.

Sulcal pits are thought to represent the first cortical folds of primary sulci during neurodevelopment. The uniform spatial distribution of sulcal pits across individuals is hypothesized to be predetermined by a human-specific protomap which is related to functional localization under genetic controls in early fetal life. Thus, it is important to characterize temporal and spatial patterns of sulcal pits in the fetal brain that would provide additional information of functional development of the human brain and crucial insights into abnormal cortical maturation. In this paper, we investigated temporal patterns of emergence and spatial distribution of sulcal pits using 48 typically developing fetal brains in the second half of gestation. We found that the position and spatial variance of sulcal pits in the fetal brain are similar to those in the adult brain, and they are also temporally uniform against dynamic brain growth during fetal life. Furthermore, timing of pit emergence shows a regionally diverse pattern that may be associated with the subdivisions of the protomap. Our findings suggest that sulcal pits in the fetal brain are useful anatomical landmarks containing detailed information of functional localization in early cortical development and maintaining their spatial distribution throughout the human lifetime.

The Congenital Heart Disease Brain: Prenatal Considerations for Perioperative Neurocritical Care.

Altered brain development has been highlighted as an important contributor to adverse neurodevelopmental outcomes in children with congenital heart disease. Abnormalities begin prenatally and include micro- and macrostructural disturbances that lead to an altered trajectory of brain growth throughout gestation. Recent progress in fetal imaging has improved understanding of the neurobiological mechanisms and risk factors for impaired fetal brain development. The impact of the prenatal environment on postnatal neurological care has also gained increased focus. This review summarizes current data on the timing and pattern of altered prenatal brain development in congenital heart disease, the potential mechanisms of these abnormalities, and the association with perioperative neurological complications.

Early-Emerging Sulcal Patterns Are Atypical in Fetuses with Congenital Heart Disease.

Fetuses with congenital heart disease (CHD) have third trimester alterations in cortical development on brain magnetic resonance imaging (MRI). However, the intersulcal relationships contributing to global sulcal pattern remain unknown. This study applied a novel method for examining the geometric and topological relationships between sulci to fetal brain MRIs from 21-30 gestational weeks in CHD fetuses (n = 19) and typically developing (TD) fetuses (n = 17). Sulcal pattern similarity index (SI) to template fetal brain MRIs was determined for the position, area, and depth for corresponding sulcal basins and intersulcal relationships for each subject. CHD fetuses demonstrated altered global sulcal patterns in the left hemisphere compared with TD fetuses (TD [SI, mean ± SD]: 0.822 ± 0.023, CHD: 0.795 ± 0.030, P = 0.002). These differences were present in the earliest emerging sulci and were driven by differences in the position of corresponding sulcal basins (TD: 0.897 ± 0.024, CHD: 0.878 ± 0.019, P = 0.006) and intersulcal relationships (TD: 0.876 ± 0.031, CHD: 0.857 ± 0.018, P = 0.033). No differences in cortical gyrification index, mean curvature, or surface area were present. These data suggest our methods may be more sensitive than traditional measures for evaluating cortical developmental alterations early in gestation.